DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. The Amendment filed on May 4, 2026, has been received and entered.
Claim Disposition
3. Claims 2-3, 6-7, 10-11, 13-14, 16, 18-21, 25-29, 32-34, and 36-38 are cancelled. Claims, 1, 4-5, 8-9, 12, 15, 17, 22-24, 30-31 and 35 are pending. Claims 1, 4-5, 8-9, 12, 17 and 22 are under examination. Claims 23-24, 30-31 and 35 are withdrawn fromfurther consideration pursuant to 37 CFR 1.12(b), as being drawn to a non-electedinvention, there being no allowable generic or linking claim.
Claim objection
4. Claims 1, 4-5, 8-9, 12, 17 and 22 are objected to for the following informalities:
For clarity and precision of claim language it is suggested that claim 1 is amended to recite, “ A method of producing an antibody composition, [[said method]] comprising: obtaining an antibody sample from a cell culture with cells expressing the antibody; treating the sample with an enzyme that cleaves the antibody….;determining relative unpaired afucosylated glycan content and/or relative unpaired high mannose glycan content of the sample of antibody……”. The claim language needs a method step that matches the permeable objective. The dependent claims hereto are also included.
For clarity it is suggested that claim 12 is amended to recite, “….further comprising maintaining [[a]] the cell culture comprising cells expressing antibodies…” The dependent claims hereto are also included.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claims 1, 4-5, 8-9, 12, 17 and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention is directed to “a method of producing an antibody composition, said method comprising determining the relative unpaired afucosylated glycan content and/or the relative unpaired high a mannose glycan content of sample of the antibody composition and selecting the antibody composition for downstream processing…..” (see claim 1 in its entirety). The claimed invention is not adequately described and encompasses a large variable genus of antibodies, antibody composition, enzymes, modifications, modifying conditions, target range and modified cell culture.
The claimed invention is very broad and not commensurate in scope with the disclosure in the specification. The invention is not adequately described, for example the method is directed to producing an antibody composition (see claim 1 preamble) and (i) recites ‘of a sample of the antibody composition’, therefore the method already encompasses an antibody composition and is selecting the antibody composition, not necessarily producing it (see claim 1(ii)). Moreover, there are no indicia as to what specific antibody, for example IgG or IgM etc. Further, the method involves modifying one or more conditions of the cell culture to modify the relative unpaired afucosylated glycan content and/or the relative unpaired high mannose glycan content of an undisclosed antibody. An ordinary skilled artisan cannot decipher which conditions are modified, how they are modified and how the cell culture is modified to therefore be able to modify the unpaired afucosylated glycan content etc. How does the cell culture modify the end result and what cells are being manipulated (no specific organism provided), the claimed invention is not adequately described or defined in the claim language. The claimed invention is overly broad and the method steps does not necessarily lead to or align with the method objective. The invention also encompasses having a target range, but the variables around the target range are unknown, thus hard to figure out what specific range is being targeted. If the target is unknown, how do you know when it is achieved and what conditions were modified to achieve it. The claimed invention also denotes repeating the modifying, however, there’s insufficient description to determine what is being repeated based on the claim language. The language in for example claim 1(ii) recites, “modifying one or more cell culture conditions based on the relative unpaired afucosylated glycan content and/or the relative unpaired high mannose glycan content and there is no defined modification or mechanism to get the results desired. Can any enzyme be utilized to treat any antibody composition to cleave the antibody heavy chain at a site N-terminal to the hinge region disulfide linkages to form fragments of any antibody as claimed? It is noted that claim 17 provides a sequence to be cleaved, however, does not rectify all the missing information in the lead claims. The invention also encompasses a variety of glycan moieties with no further guidance in the claims and the limitations of the specification cannot be read into the claims.
Thus the claimed invention is overly broad and not commensurate in scope with the disclosure in the specification and therefore, is not adequately described. No correlation is made between structure and function for the protease of the claimed invention, and does not demonstrate possession of the large genus. The specification fails to provide a representative number of species for the claimed genus to show that applicant was in possession of the claimed genus. A representative number of species means that the species, which are adequately described, are representative of the entire genus.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by
functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed" (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed" (See Vas-Cath at page 1116). The skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993).
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claims 1, 4-5, 8-9, 12, 17 and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 and the dependent claims hereto are indefinite for the recitation of “modifying one or more cell culture conditions” because it is unclear what conditions and what modifications are desired to produce the right outcome. In addition, claim 1 is indefinite for the recitation of “the sample is from a cell culture” because this is vague and undefined since there are no indicia as to what cells are being cultured to provide the antibody.
Claim 4 lacks clear antecedent basis for the recitation of “taking a second sample”, the claim language should be “further comprising taking a second sample”, because the prior method steps are geared to towards a single sample, thus no antecedent basis for this language.
Claim 12 lacks clear antecedent basis for ‘the downstream processing’. The dependent claims hereto are also included.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
7. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
8. Claim(s) 1, 4-5, 8-9, 12, 17 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shatz, (2013, of record in the application) in view of Lippold, (2019, of record in the application), Liu, (2015, of record in the application) and Dong (2016, of record in the application).
The effect of fucosylation/afucosylation on FcyRilla-binding and thus ADCC is well understood in the art. It is also well established that antibodies are produced in cell culture with heterologous glycosylation (i.e., That antibody-species can be fully glycosylated, fully aglycosylated, hemi-glycosylated (i.e, only one of two Fc regions carries a glycan), fully fucosylated, fully afucosylated, hemi-fucosylated (i.e. only two of the glycans carries a fucose). A large number of prior art documents determine fucosylation/afucosylation-status of antibody species in a composition by means of mass- spectrometry. Most of these release glycans from protein, whereupon information is lost about how fucosylated/afucosylated glycans were originally paired. However, a number of prior art documents analyze glycan pairing by performing MS on intact antibodies or intact antibody-Fc dimers. Shatz is one such reference, which discloses that fully glycosylated but hemi-fucosylated (i.e, unpaired afucosylated, asymmetrically fucosylated antibody-form suffices to induce ADCC almost to the level of fully afucoslyated antibody (see entire document, especially abstract and Tables 1-2). Glycoforms of the antibodies are attributed based on Ms-weight of full-length antibody (see Fig 4) with weights or ca. 148,000 i.e., Glycans are not released. This allows for distinguishing between fully/hemi-fucosylated forms. The ADCC activity is not expressly disclosed. The secondary reference by Lippold discloses a method for resolving glycoforms of antibodies, and correlating this to FcyRIIIa-affinity and thus ASCC (se FIG 1). The method is again based on determining the mass of intact glycosylated antibodies Mwt. ca. 148,000) without releasing the glycans first. The secondary reference acknowledges that antibodies are produced in heterologous glycoforms, and that some of these are fully-glycosylated but hemi-fucosylated (i.e., FIG 1B). Moreover a tertiary reference discloses that antibodies are produced with heterologous glycoforms, including complex (CO) fucosylated and high mannose (HM) forms, and that these are produced inter alia fully-glycosylated, hemi-glycosylated, or fully aglycosylated forms (FIG 1). Dong teaches that glycosylation is a CQA of antibody-products since it affects inter alia ADCC. Controlling glycosylation is particularly important and the Dong reference disclose an in-line process for monitoring product quality during culturing, and the effect of various process parameters thereon. The method quantifies the various glycoforms by mass spectrometry (see FIG 2 and page 8674, right col.). Process parameters were monitored on product quality and glycosylation was monitored daily. It was noted that the process could be used to detect undesired shifts in product quality, which may allow correction or adjustment of related parameters to maintain the desired ranges to achieve target product quality (see pages 8678, left column).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed invention as a whole because the combined teaching of the references render the claimed invention as obvious. One of ordinary skill in the art would be motivated to combine the references because they are analogous art. The primary reference discloses the claimed composition the remaining limitations are disclosed in the subsequent references. Moreover, the Supreme Court pointed out in KSR, “a patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 127 S. Ct. at 1741. The Court thus reasoned that the analysis under 35 U.S.C. 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the “inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 1741. The Court further advised that “[a] person of ordinary skill is…a person of ordinary creativity, not an automation.” Id. at 1742. Therefore, the claimed invention was obvious to make and use at the time the invention was made and was prima facie obvious.
Basis For NonStatutory Double Patenting
9. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
10. Claims 1, 4-5, 8-9, 12, 17 and 22 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-32, of U.S. Application No. 19/475810. An obvious-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claim(s) because the examined claim is either anticipated by, or would have been obvious over, the reference claim(s). See In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); and In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985). Although the conflicting claims are not identical, they are not patentably distinct from each other.
The instant application claims are directed to a method of producing an antibody composition (see claim 1 in its entirety). The copending application claims are drawn to a method of determining the relative unpaired glycan content of an IgG antibody composition. The two sets of claims differ because the instant claims recite generically “antibody” and the copending claims recite a specific antibody (IgG), thus the copending claims are a species of the genus claimed instantly. The dependent claims are also obvious over the instant claims.
Although the scope of the two sets of claims differs, the two sets of claims are an obvious variation of each other, thus prima facie obvious. This is a provisional obvious type double patenting rejection.
Response to Arguments
11. Applicant’s comments have been considered in full. Withdrawn objections/rejections will not be discussed herein as applicant’s comments are moot. Note that the rejections of record remain, however, have been modified to reflect changes made to the claims.
Applicant traverses the rejection under 112, first paragraph by stating that claim 1 has been amended to recite the antibody is expressed in cells and obtained from cell culture. This argument is not persuasive because the claimed invention is still directed to a large genus of antibodies and cells. This amendment did not rectify issues raised such as what antibody, what conditions are modified etc. The method objective is to produce an antibody composition and the first step already has the antibody composition which is being utilized to determine unpaired afucosylated glycan content, seems more like ‘a method of determining unpaired afucosylated glycan content in an antibody composition”. The claim language is overly broad and not adequately described, some amendments made raises new issues but does not obviate this ground of rejection.
Note that the Obvious Type Double Patenting rejection remains for the reasons stated above and because applicant did not file a Terminal Disclaimer or provide any arguments/amendments to overcome this ground of rejection.
Regarding the rejection under 103, applicant separately attacks the references when the combined teaching renders the claimed invention as obvious. Applicant also indicates that the claimed invention which remains broad and vague is not taught, however, the 103 statute requires a mere teaching or suggestion. Shatz discloses that fully glycosylated but hemi-fucosylated (i.e, unpaired afucosylated, asymmetrically fucosylated antibody-form) suffices to induce ADCC almost to the level of fully afucoslyated antibody. The tertiary reference discloses that antibodies are produced with heterologous glycoforms, including complex (CO) fucosylated and high mannose (HM) forms, and that these are produced inter alia fully-glycosylated, hemi-glycosylated, or fully aglycosylated forms (FIG 1). Moreover, Dong teaches that glycosylation is a CQA of antibody-products since it affects inter alia ADCC. Controlling glycosylation is particularly important and the Dong reference disclose an in-line process for monitoring product quality during culturing, and the effect of various process parameters thereon. In KSR v Teleflex (500 US 398 2007) (pages 12-13) " ... the Court has held that a "when a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one(emphasis added). If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill." Thus, applicant’s comments are not persuasive and the references remain relevant. Applicant is urged to contact the examiner to reduce the remaining issues.
Conclusion
12. No claims are presently allowable.
13. Applicant’s amendment necessitated the new/modified ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOPE A ROBINSON whose telephone number is (571) 272-0957. The examiner can normally be reached 9-5pm on Monday to Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HOPE A ROBINSON/Primary Examiner, Art Unit 1652
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